Project 2 - Genetic variations linked to the aging hippocampus

项目2总结 当前建议的主要焦点是识别影响情景记忆功能的遗传因素 通过检测与衰老变化相关的一组特定基因，在认知健康的老年人中 海马体。认知健康人群记忆功能分子通路的鉴定 人们希望个体能够准确地确定预防或延缓认知衰退的机制，这可能是不同的。 来自对认知障碍或痴呆症受试者的研究确定的那些。 在最近一项旨在分离老化的人齿状回(DG)与年龄的分子相关性的研究中， 与记忆丧失相关，这一P50应用程序的研究人员发现，在人类 17个基因的DG表达。显示出最强关联的基因(RbAp48)的丰度增加 老年小鼠的DG伴随着记忆能力的改善(Pavlopoulos等人。SCI，Transl Med. 2013年8月28日；5(200)：200-115)。RbAp48在组蛋白乙酰化、转录调控中发挥多重作用 和环磷酸腺苷(CAMP)蛋白激酶A(PKA)cAMP反应元件结合 蛋白1(CREB1)途径是正常海马区功能和衰老所必需的。在最初的分析中，我们测试了 RbAp48、CREB1和CREBBP基因变异与小鼠情景记忆功能的关系 认知健康的老年人的大样本。与这个组蛋白通路牵涉到 记忆功能，我们发现认知健康的老年人携带这些基因的特定变异显示 与非携带者相比，平均情节记忆功能明显更好。 本项目的主要目的是进一步阐明情景记忆功能的遗传基础。 通过探索显示年龄的17个基因的完整列表中的变异之间的关联，获得认知健康的个体。 情景记忆相关基因CREB1通路在DG中的表达变化 在认知健康的几个独立队列中，这些途径之外的基因的额外变异 并通过有针对性的重新测序来识别特定的遗传变异。我们的目标是跟进和 通过在几个独立队列中进行基因分型以及生物信息学和 生物物理分析评估已识别的突变对蛋白质结构、水平和功能的影响。

PROJECT 2 SUMMARY The main focus of the current proposal is the identification of genetic factors influencing episodic memory function in cognitively healthy elderly by examining a specific set of genes associated with changes in the aging hippocampus. The identification of molecular pathways underlying memory function in cognitively healthy individuals is expected to pinpoint mechanisms for preventing or delaying cognitive decline that might be distinct from those identified by studies of subjects with cognitive impairment or dementia. In a recent study aiming to isolate molecular correlates of the aging human dentate gyrus (DG) and age- related memory loss, investigators of this P50 application identified substantial age-related changes in the human DG expression of 17 genes. Increasing abundance of the gene showing the strongest association (RbAp48) in the DG of aged mice was accompanied by improved memory performance (Pavlopoulos et al. Sci Transl Med. 2013 Aug 28;5(200):200ra115). RbAp48 plays multiples roles in histone acetylation, transcriptional regulation and the cyclic adenosine monophosphate (cAMP) protein kinase A (PKA) cAMP response element binding protein 1 (CREB1) pathway required for normal hippocampal function and aging. In initial analyses we tested whether genetic variants in RbAp48, CREB1 and CREBBP were associated with episodic memory function in large samples of cognitively healthy elderly. Consistent with the idea that this histone pathway is implicated in memory function, we found that cognitively healthy elderly carrying specific variants in these genes showed significantly better average episodic memory function when compared to non-carriers. The overarching aim of this project is to further elucidate the genetic basis of episodic memory function in cognitively healthy individuals by exploring the association of variants in the full list of 17 genes showing age- related expression changes in the DG with episodic memory function, three genes acting in the CREB1 pathway and additional variants in genes outside these pathways in several independent cohorts of cognitively healthy individuals, and to identify the specific genetic variants by targeted resequencing. We aim to follow-up and validate identified mutations by genotyping in several independent cohorts as well as bioinformatics and biophysical analyses assessing the effect of identified mutations on protein structure, level and function.